Field of Invention
The present invention relates to a chemical pharmaceutical field, and more particularly to a 6-deoxy-6-thioether-amino acid cyclodextrin derivative and a preparation method thereof, mainly comprising a 6-deoxysulfinyl-6-thioether-amino acid cyclodextrin derivative, a 6-deoxysulfonyl-6-thioether-amino acid cyclodextrin derivative, preparation methods thereof, and a method for antagonizing muscular relaxation comprising administrating a drug comprising a therapeutically effective amount of the 6-deoxy-6-thioether-amino acid cyclodextrin derivative, wherein the drug is able to rapidly reverse the muscular relaxation induced by muscular relaxant and have features of high pharmaceutical security, available reactants and low cost.
Description of Related Arts
In 1986, it was reported on J.A.C.S. that (o-carboxyphenyl)thio cyclodextrin was synthesized by Tubashi. I.; in 1995, it was reported that carboxymethylthio cyclodextrin was synthesized by Guillo. F.; and in 1996, Baer. H. H. and Santoyo-Gonzalez. F. prepared 2,3-dihydroxypropylthio cyclodextrin having a following structural formula.

A Chinese patent application, CN1402737, disclosed a preparation method of a similar compound having a following chemical structural formula (A):

wherein m is one member selected from a group consisting of 0, 1, 2, 3, 4, 5, 6 and 7; n is one member selected from a group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; a sum of m and n is 7 or 8;
R is (C1-C6)alkylene, optionally substituted with 1-3 OH groups or (CH2)r-phenylene-(CH2)t-, wherein r and t are independently 0-4; and
X1 is one member selected from a group consisting of COOH, CONHR6, NHCOR7, SO2OH, PO(OH)2, O(CH2—CH2—O)u-H, OH and tetrazol-5-yl; R6 is H or (C1-3)alkyl; R7 is carboxyphenyl; u is 1-3.
The compound mentioned above excludes substitutes having structures of amino acids.
Sugammadex is a species of 6-thioether cyclodextrin derivative disclosed in a Chinese patent application CN1402737. In July 2007, sugammadex (Bridion) of Schering Plough Company came into the market. The sugammadex is for reversing effects of rocuronium bromide and vecuronium bromide which are generally used as neuromuscular blocking drugs. The sugammadex is able to readily reverse the effects of the rocuronium bromide used for adults and generally reverse the effects of the vecuronium bromide used for children and teenagers between 2 and 17 years old.
However, the sugammadex has a main advantage of mere capability to antagonize the antagonist effect on the muscular relaxation induced by the rocuronium bromide and the vecuronium bromide, while having poor reversal or antagonism performance against other common muscular relaxants, such as pancuronium bromide, pipecuronium bromide, dacuronium bromide and quindonium bromide.
A Chinese patent application CN101591402 disclosed a structure (B) of 6-deoxy thioether amino acid cyclodextrin derivative and a preparation method thereof, wherein the preparation method thereof comprises firstly synthesizing halogenated cyclodextrin and then condensing mercapto compound with the halogenated cyclodextrin in presence of alkali, so as to obtain the 6-deoxy thioether amino acid cyclodextrin derivative.

In the structure (B), d is one member selected from a group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8; e is one member selected from a group consisting of 1, 2, 3, 4, 5, 6, 7, 8 and 9; a sum of d and e is one member selected from a group consisting of 6, 7, 8 and 9;
q is 1 or 2;
R0 is (C1-C6)alkylene, optionally substituted by 1-3 OH groups or (CH2)x-phenylene-(CH2)g-, wherein x is one member selected from a group consisting of 0, 1, 2, 3 and 4 and g is one member selected from a group consisting of 0, 1, 2, 3 and 4; and
X is one member selected from a group consisting of COOH, CONHR8, NHCOR9, SO2OH, PO(OH)2, O(CH2—CH2—O)h-H, OH and tetrazol-5-yl, wherein R8 is H, (C1-3)alkyl or (C1-3)alkyl containing COOH; R9 is carboxyphenyl; and h is 1, 2 or 3.
Disclosed by the Chinese patent application CN101591402, a method for antagonizing muscular relaxation comprising administrating a drug comprising a therapeutically effective amount of a compound is able to reverse the muscular relaxation induced by human or animal muscular relaxants and has reversal and antagonism effects on the muscular relaxation induced by the muscular relaxants.
The compound of the Chinese patent application CN101591402 has improved selectivity, but excludes substitutes having structures of α-position amino acids and derivatives thereof.